Holmium complex with phospholipids as 1H NMR temperature probe for membrane systems.

The temperature dependence of the lanthanide-induced chemical shifts (LISs) was studied for the systems containing 1-palmitoyl-2-oleoylphosphatidylcholine (POPC)-Ho, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)-Ho and 1,2-dimyristoyl-sn-glycero-3-phosphorylcholine (DMPC)-Ho in unilamellar liposomes. In the POPC-Ho system, anti-Curie dependence of LISs is observed, same as previously observed in POPC-Pr system. In the DPPC- and DMPC-Ho systems, temperature features are observed which are probably connected with phase transition.

Ascorbate-and iron-driven redox activity of Dp44mT and Emodin facilitates peroxidation of micelles and bicelles.

BACKGROUND: Iron (Fe)-induced oxidative stress leads to reactive oxygen species that damage biomembranes, with this mechanism being involved in the activity of some anti-cancer chemotherapeutics. METHODS: Herein, we compared the effect of the ligand, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), or the potential ligand, Emodin, on Fe-catalyzed lipid peroxidation in cell membrane models (micelles and bicelles). These studies were performed in the presence of hydrogen peroxide (H2O2) and the absence or presence of ascorbate. RESULTS: In the absence of ascorbate, Fe(II)/Emodin mixtures incubated with H2O2 demonstrated slight pro-oxidant properties on micelles versus Fe(II) alone, while the Fe(III)-Dp44mT complex exhibited marked antioxidant properties. Examining more physiologically relevant phospholipid-containing bicelles, the Fe(II)- and Fe(III)-Dp44mT complexes demonstrated antioxidant activity without ascorbate. Upon adding ascorbate, there was a significant increase in the peroxidation of micelles and bicelles in the presence of unchelated Fe(II) and H2O2. The addition of ascorbate to Fe(III)-Dp44mT substantially increased the peroxidation of micelles and bicelles, with the Fe(III)-Dp44mT complex being reduced by ascorbate to the Fe(II) state, explaining the increased reactivity. Electron paramagnetic resonance spectroscopy demonstrated ascorbyl radical anion generation after mixing ascorbate and Emodin, with signal intensity being enhanced by H2O2. This finding suggested Emodin semiquinone radical formation that could play a role in its reactivity via ascorbate-driven redox cycling. Examining cultured melanoma cells in vitro, ascorbate at pharmacological levels enhanced the anti-proliferative activity of Dp44mT and Emodin. CONCLUSIONS AND GENERAL SIGNIFICANCE: Ascorbate-driven redox cycling of Dp44mT and Emodin promotes their anti-proliferative activity.

Effect of glycyrrhizic acid on phospholipid membranes in media with different pH.

Glycyrrhizic acid (GA) is the active ingredient in licorice root, which exhibits a wide range of biological activities, including anti-inflammatory and antiviral activities. In particular, the virus-inhibiting effect of GA on SARS-associated coronavirus was demonstrated. In addition, GA was found to be capable of increasing bioaccessibility of other drugs when used together. All these effects can be based on the ability of GA to incorporate into cell membranes and change their physical and functional properties. One of the possible mechanisms of the antiviral action of GA against COVID-19 is also considered to be the prevention of fusion of the virus envelope with the plasma membrane of the host cell. The interaction of GA with model lipid membranes was studied by the NMR method. Different factors influencing the incorporation of the GA molecule into the lipid bilayer (phospholipid structure, pH of the medium) were examined.

Glycyrrhizin-induced changes in phospholipid dynamics studied by 1H NMR and MD simulation.

Phospholipid bilayer constitutes the basis of the cell membrane. Any changes in its structure and dynamics could significantly affect the properties and functions of the cell membrane and associated proteins. It could, in its turn, affect the mechanism and strength of drug-membrane interaction. Phase transitions in lipid bilayer play an important role in cell life and in transmembrane transport of ions and drug molecules. In the present study we have tried to clarify the mechanism of glycyrrhizin bioactivity by the study of its influence on the lipid dynamics and phase transition of the lipid bilayer. For this purpose, a combination of nuclear magnetic resonance (NMR) and molecular dynamic (MD) simulations was used. Glycyrrhizin is the saponin extracted from licorice root. It displays a wide spectrum of biological activity and is frequently used in traditional medicine since ancient times. Now glycyrrhizin attracts additional attention as a novel multifunctional drug delivery system. We have established that glycyrrhizin interaction with dipalmitoylphosphatidylcholine lipid bilayers leads to changes in lipid mobility and phase transition temperature. NMR and MD results demonstrated that a glycyrrhizin molecule is able to integrate into a lipid bilayer and form stable aggregates inside. We hypothesize that surface curvatures caused by local changes in the lipid composition and the presence of phase boundaries might affect the permeability of the cell membrane.

Glycyrrhizic acid as a multifunctional drug carrier - From physicochemical properties to biomedical applications: A modern insight on the ancient drug.

Glycyrrhizic acid is the main active component of Licorice root which has been known in traditional Chinese and Japanese medicine since ancient times. In these cultures glycyrrhizic acid (GA) is one of the most frequently used drugs. However, only in 21-st century a novel unusual property of the GA to enhance the activity of other drugs has been discovered. The review describes briefly the experimental evidences of wide spectrum of own biological activities of glycyrrhizic acid as well as discusses the possible mechanisms of the ability of GA to enhance the activity of other drugs. We have shown that due to its amphiphilic nature GA is able to form self-associates in aqueous and non-aqueous media, as well as water soluble complexes with a wide range of lipophilic drugs. The main purpose of our review is to focus reader's attention on physicochemical studies of the molecular mechanisms of GA activity as a drug delivery system (DDS). In our opinion, the most intriguing feature of glycyrrhizic acid which might be the key factor in its therapeutic activity is the ability of GA to incorporate into the lipid bilayer and to increase the membrane fluidity and permeability. The ability of biomolecules and their aggregates to change the properties of cell membranes is of great significance, from both fundamental and practical points of view.

Natural Poly- and Oligosaccharides as Novel Delivery Systems for Plant Protection Compounds.

To increase the bioavailability of plant protection products, we have applied a new approach based on noncovalent association with natural water-soluble polysaccharides and oligosaccharides as delivery systems (DSs). The mechanochemical technique has been applied to prepare the solid-state nanodispersed compositions of antidote 1,8-naphthalic anhydride (NA) with arabinogalactan, sodium salt of carboxymethylcellulose, and glycyrrhizin as DSs. The effect of DSs on the solubility and the penetration of NA into the seeds of barley and wheat has been investigated by various physicochemical techniques. All DSs considerably enhance the solubility of NA and improve its penetration into the grain. The influence of polysaccharides and oligosaccharides on artificial lipid membranes was studied by the NMR relaxation method. It was concluded that the effect of polysaccharides and oligosaccharides on the penetration efficacy of plant protection products might be associated with the detected solubility enhancement and the affinity of DSs to the surface of cell membranes.

Spectroscopic and molecular dynamics characterization of glycyrrhizin membrane-modifying activity.

Glycyrrhizic acid (GA) is a triterpene glycoside extracted from licorice root. Due to its amphiphilicity GA is capable of forming complexes with a variety of hydrophobic molecules, substantially increasing their solubility. GA can enhance the therapeutic effects of various drugs. It was hypothesized that the increased bioavailability of the drug by GA is not only due to increased solubility, but also to enhancement of drug permeability through cell membranes. In this study the interaction of GA with POPC liposomes and model DOPC, POPC and DPPC bilayers was investigated by NMR with addition of shift reagents and MD simulations. This work helps to better understand the mechanism of enhanced drug bioavailability in the presence of GA. NMR and MD reveal that GA does penetrate into the lipid bilayer. NMR shows that GA changes the mobility of lipids. GA is predominantly located in the outer "half-layer" of the liposome and that the middle of the hydrophobic tails is the preferred location. GA freely passes through the bilayer surface to the inner part bringing a few water molecules. Also both approaches indicate pore formation in the presence of GA. The GA interaction with membranes is an additional aspect of the biological activity of GA-based drug delivery systems.

Influence of glycyrrhizin on permeability and elasticity of cell membrane: perspectives for drugs delivery.

Glycyrrhizin or glycyrrhizic acid (GA) - triterpene glycoside extracted from licorice root - has been intensively studied over the past decade and is considered to be a potential drug delivery system. Glycyrrhizin was found to enhance the therapeutic effect of various drugs; however the detailed mechanism of these effects is still unknown and attracts the attention of researchers. In this work, we have made an attempt to clarify the mechanism of Glycyrrhizin activity on molecular and cellular level. The influence of GA on the functional properties of biomembranes was investigated via NMR spectroscopy and atomic force microscopy (AFM) using human erythrocytes as a model system. GA was shown to increase the permeability (about 60%) and to decrease elasticity modulus of cell membranes (by an order of magnitude) even in micromolar concentrations. Changes on the erythrocyte surface were also detected by AFM. These results could provide a new insight on the mechanism of bioavailability enhancement of some drugs in the presence of glycyrrhizin, as well as the mechanism of its own biological activity. The role of cholesterol-glycyrrhizin binding in the observed effects is also discussed.